At present the only treatment for beta-thalassemia (Cooley's anemia) is a transfusion regimen. This leads to accumulation of iron and an ultimately fatal hemosiderotic condition. To prevent cell damage the excretion of iron must be promoted. This is accomplished by administering agents which form excretable iron chelates, but present agents have not proved totally acceptable or successful. A number of chelating agents with a very high affinity constant for iron have been developed. However, ability to promote iron excretion is not necessarily strongly correlated with affinity constants. We hypothesize that metabolism of the chelating agents plays a major role in determining their usefulness as drugs and that consideration of both metabolism and affinity constants may lead to better predictability of useful drugs and to suggestions for the design of better agents. Such an understanding would be of clinical importance as over 3 million people are estimated to be afflicted with clinically significant thalassemia. We therefore propose to study the in vitro and in vivo metabolism of a hexadentate chelator with a very high affinity for iron but modest in vivo activity, a hexadentate chelator with intermediate affinity but excellent activity and the tridentate analog of the former compound. The metabolism of both the chelating agent and of the preformed iron chelate will be studied. Radiolabeled chelating agents will be synthesized and incubated with liver cells and fractions. Major metabolites will be isolated (by hplc) and identified (by ms and 13C or 1H-nmr). In vivo studies with radiolabeled compound will be done in normal and hypertransfused animals. Metabolites will be identified and concentrations of parent, metabolites and iron in blood and tissues will be determined. Suggestions for more useful agents will be developed.